We have continued studies to evaluate and characterize antibodies to HIV envelope which interfere with the interaction of HIV with the cellular receptor CD4. These antibodies comprise 20% of the total antibody response to soluble gp120 and are present in concentrations equivalent to 50-200 ug/ml of soluble CD4. These CD4 blocking antibodies show cross reactivity between different laboratory isolates, but have highest binding to the HIV MN strain in cell binding gp120-CD4 assays. The majority of CD4 blocking antibodies are directed against the CD4 binding site on gp41- dissociated gp120. This analysis has discovered that the gp120 CD4 binding site as recognized by CD4-blocking antibodies differs dramatically between gp120 envelope in solution and gp120 attached to gp41 on the cell/virus surface. The data suggests that antibodies which interfere with CD4-gp120 interactions may select in vivo viral stains resistant to soluble CD4 therapy. These findings also theoretically support vaccine and immunotherapeutic approaches based on cellular expression of viral antigens as the most effect means of generating protective immunity.